The LCDO's Oral Cancer Program investigates etiology, diagnosis, treatment and prevention of oral tumors, placing a special emphasis on the most prevalent oral cancer, squamous cell carcinoma (SCC). One component of this effort involves identification of molecules that uniquely describe stages of progression from normal to malignant. The presence or absence of such molecules can be useful information for (i) diagnosis, (ii) in determining appropriate treatment modalities and (iii) in assessing the efficacy of chemoprevention protocols. Among the growth promoting molecules identified to date as markers of malignancy are the receptor for epidermal growth factor in combination with one or more of its agonists. Of the growth regulatory class of molecules, p53 is mutated and nonfunctional in a high percentage of SCCs, and an inhibitor of G1 cyclin kinases, p16, is compromised in all SCC cell lines studied to date. The expression of a second cyclin kinase inhibitor, p15, is less frequently altered. Furthermore, the ability of tumor cells to upregulate expression of a third cell cycle regulator, p21, in response to DNA damage or growth factor receptor signaling, is altered. Thus, the laboratory's repertoire of molecular markers heralding the malignant state continues to expand, and the functional consequences of dysregulation of these molecules during tumor development is becoming apparent. Assays developed for such molecules will be useful to others clinically and to us as intermediate biomarkers for assessing progress in chemoprevention settings, as well as providing an insight into the molecular mechanisms of oral squamous cell carcinogenesis.